Prostate Cancer (PCa) is the most commonly occurring malignancy in men in the USA and several other developed countries. A man's chance of developing PCa significantly increases with increasing age;therefore, it is important to define the causal connection between mechanisms of aging and PCa. In a recent study, we have found Sirti, a longevity-associated histone deacetylase, is overexpressed in PCa cells and tissues and its inhibition causes a decrease in cell growth and viability and increase in senescence in PCa cells. Further, our recent exciting preliminary data has shown that melatonin, a pineal hormone and a widely used supplement among cancer patients, is a potent inhibitor of Sirti. Melatonin synthesis by the human body displays a circadian rhythm that is generated by a circadian clock located in the hypothalamus. Studies have shown that melatonin possesses chemopreventive, oncostatic and tumor inhibitory effects in a variety of experimental models. Further, melatonin has a potential to increase the efficacy and decrease the side effects of chemotherapy in adjuvant settings. In vitro studies have also indicated that melatonin possesses antiproliferative effects against human PCa cells. Importantly Sirti has been found to be required for circadian transcription of several core clock genes (Bmall, Rory, Per2, and Cryl) suggesting that Sirti connects cellular metabolism to the circadian core clockwork circuitry. Melatonin has been shown to control a variety of clock genes which have recently been linked to cancer. This proposal capitalizes on these novel observations and the central hypothesis of the work proposed in this application is that melatonin will impart anti-proliferative as well as chemopreventive effects against prostate cancer via Sirti inhibition-mediated modulations in circadian core clockwork circuitry. The following specific aims are proposed;1) To establish a cause-and-effect association between the anti-proliferative effects of melatonin and Sirti in human PCa cells;2) To determine the involvement of circadian rhythm genes as a mechanism of the anti-proliferative effects of melatonin in PCa cells;and 3) To determine if melatonin will impart anti-proliferative and/or chemopreventive effects against PCa via Sirti inhibition-mediated modulations in clock genes in vivo in transgenic adenocarcinoma mouse prostate (TRAMP) mice, which mimics the features of human disease. We believe that successful completion of this proposal will establish i) the potential of melatonin (a widely used CAM approach) against PCa, and ii) a novel molecular mechanism(s) of the biological effects of melatonin. This may help in designing novel strategies for the management of PCa.